The overall goal of this research is to understand the initial interactions of Orthomyxoviruses and Paramyxoviruses with their host cells. Our hypothesis is that there are likely to be interactions that are common to several pathogens, and blocking of these common receptors by decoy molecules may enable a single strategy to be used for several unrelated pathogens, including some that are on the list of potential Biotorrorism agents. Influenza viruses bind to sialic acids through the viral hemagglutinin glycoprotein (HA), and new virions are released by the sialidase activity of the viral neuraminidase glycoprotein (NA). In Paramyxoviruses these functions are on a single protein (HN). The binding interaction has been seen in crystal structures of HA bound to sialylated oligosaccharides and HN bound to sialic acid, but the detailed specificity remains unknown. Our Specific Aims are to answer: 1. What is the binding affinity of human influenza and parainfluenza viruses to sialylated oligosaccharides? 2. Do the specificities determined with ohgosaccharides account for differences in hemagglutination and permissive host cells? What is the influence of the protein or lipid environment of the sialylated oligosaccharide? 3. What is the role of neuraminidase in influenza and parainfluenza virus infection? The results of these experiments will provide significant new information on how viruses interact with the outer layers of the cell glycocalyx to reach the plasma membrane and infect the cell.